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Three Part Question

In [an adult with asthma] is [nebulised beta-agonist with nebulised magnesium sulphate better than nebulsed beta-agonist alone] at [improving airflow and reducing morbidity]?

Clinical Scenario

A known asthmatic patient is brought into the emergency department with signs consistent with acute asthma. Little improvement is noted with nebulised beta-agonist therapy. You wonder if adjunctive nebulised magnesium sulphate would provide any benefit.

Search Strategy

Medline 1966-05/04 using the Ovid interface.
Repeated August 06 using Ovid interface.
Cochrane database also searched using term 'magnesium'.
[(Exp magnesium OR magnesium$.mp OR exp magnesium sulfate OR magnesium sul$.mp OR exp magnesium compounds OR magnesium compound$.mp) AND (nebulise$.mp OR nebulize$.mp OR vaporise$.mp OR vaporize$.mp OR inhal$.mp) AND (Exp asthma OR asthma$.mp OR exp bronchial spasm OR bronchial spasm.mp OR bronchospasm.mp)] Limit to human AND English language.

Search Outcome

Altogether 105 articles found of which 8 were relevant to the original question. 1 Cochrane review was found which incorporated data from 6 of the studies.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kokturk, N; Turkas, H; Kara, P; Mullaoglu, S; Yilmaz, F; Karamercan, A 2005 Turkey	26 patients with acute moderate to severe asthma included in the study. Patients but not the investigators were blinded to the treatment received.	Patients were randomised to receive either 6.25mg salbutamol with 145mg iso-osmolar magnesium sulphate (14 patients) or 6.25mg salbutalmol with isotonic saline (12 patients) via a nebuliser. Patients were discharged when PEFR was >70% predicted or admitted if PEFR not >70% predicted by 4h.	Mean duration of observation	105.71+/-72.08 for Mg/Sal group vs. 118+/-96.66 for Sal group. (NS)	No power calculations performed. Very small number of patients unlikely to detect any difference in outcome unless massive.
			Pts requiring hospital admission	1/14 in Mg/Sal group vs. 2/12 in the Sal group. (NS)
			Adverse events	2 patients receiving Mg/Sal had transient hypotension. 1 patient receiving Sal had palpitations.
Blitz, M; Blitz, S; Beasely, R; Diner, BM; Hughes, R; Knopp, JA; Rowe, BH 2005 Canada	296 patients with acute asthma in 6 trials.	4 of the trials compare magnesium sulphate and a B-agonist with a B-agonist alone.	Pulmonary function improved by Mg/B-agonist vs. B-agonist alone.	Standardised mean difference 0.23 (95% CI -0.03 to 0.50) (NS)	Small number of small heterogeneous trials make definitive conclusions difficult.
			Pulmonary functions in Mg/B-agonist vs. B-agonist alone in subgroup of patients with severe asthma.	SMD 0.55 (95% CI 0.12 to 0.98) (significant)
			Reduction in probability of admission.	RR 0.69 (95% CI 0.42 to 1.12) (NS)
			Risk of adverse events	RD 0.00 (95% CI -0.03 to 0.03)
Aggarwal, P; Sharad, S; Handa, R; Dwiwedi, SN; Irshad, M 2006 India	100 patients attending hospital with acute asthma.	Pts randomised in double-blind fashion to receive either magnesium sulphate and salbutamol (Group A) or salbutamol alone (Group B).	Peak expiratory flow rate (PEFR) at 2h	237.8 (SD=56.3) in Group A vs. 236.2 (SD=61.7) in Group B	Study underpowered to look for differences in outcome. Would have need roughly twice as many patients to have a 90% chance of detecting a 10% difference in mean PEFR.
			Number of patients requiring hospital admission	9/50 in Group A vs. 10/50 in Group B.
			Adverse events	No significant adverse events recorded.

Comment(s)

Evidence exists regarding efficacy of intravenous magnesium in bronchospasm reversal. Of the few studies that relate to nebulised magnesium in bronchospasm reversal, the samples remain small and conflicting results exist. The Cochrane review suggests that there is an overall benefit in combining magnesium sulphate with nebulised B-agonists in patients with severe asthma. There is also a non-significant trend towards lower rates of hospital admission. The authors state that 'heterogeneity between trials included in this review precludes a more definitive conclusion.' No significant adverse events are reported in any of the studies. The trials listed have used isotonic solutions of magnesium sulphate, approximately 60mg/ml or 6% solutions. There is a risk that more concentrated solutions can actually cause bronchoconstriction (Nannini, 1995).

Editor Comment

External comment received July 2004: "Please add a warning to any reader that great caution must be taken in ensuring that any nebulised magnesiun solution is isotonic we have had a near fatality as a result of inadequately diluted nebulised magnesium - will be formally reported in the literature in the near future." BET author response July 2004: "Of the published research reviewed, it was noted that predominantly iso-osmolar magnesium was administered. No study incorporated hyper-osmolar solutions however some authors did mention hypothetical outcome differences should the latter be administered. Unpublished studies were not included in this BET. Review of asthma guidelines (Australia, US, UK) do not advocate the use of nebulised magnesium and, as such, must currently be considered a research intervention."

Clinical Bottom Line

Despite a suggestion of benefit in the sub-group of patients with acute severe asthma this treatment is not advocated at this time by the current BTS/SIGN national asthma guidelines (2004). It is mentioned in the most recent edition of the BNF as an unlicensed indication for patients with acute severe asthma unresponsive to standard therapy alongside intravenous magnesium sulphate. The potential benefits of this treatment warrant further research.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Kokturk, N; Turkas, H; Kara, P; Mullaoglu, S; Yilmaz, F; Karamercan A randomised clinical trial of magnesium sulphate as a vehicle for nebulized salbutamol in the treatment of moderate to severe asthma attacks Pulmonary Pharmacology and Therapeutics 2005; (18) p416-421
2. Blitz, M; Blitz, S; Beasely, R; Diner, BM; Hughes, R; Knopp, JA; Rowe, BH Inhaled magnesium sulfate in the treatment of acute asthma Cochrane Database of Systematic Reviews 2005; Issue 4. Art No.:CD003898
3. Aggarwal, P; Sharad, S; Handa, R; Dwiwedi, SN; Irshad, M Comparison of nebulised magnesium sulphate and salbutamol combined with salbutamol alone in the treatment of acute bronchial asthma: a randomised study Emergency Medicine Journal 2006; 23: p358-362
4. Nannini, LJ Jr Hyperosmolar challenge by means of a jet nebulizer in asthma. A new method. Am J Respir Crit Care Med 1995; 151: A402